A. Anatomy of the Human Eye
In human beings, the anatomy of the eye includes a “vitreous body” which occupies approximately four fifths of the cavity of the eyeball, behind the lens. The vitreous body is formed of gelatinous material, known as the vitreous humor. Typically, the vitreous humor of a normal human eye contains approximately 99% water along with 1% macromolecules including: collagen, hyaluronic acid, soluble glycoproteins, sugars and other low molecular weight metabolites.
The retina is essentially a layer of nervous tissue formed on the inner posterior surface of the eyeball. The retina is surrounded by a layer of cells known as the choroid layer. The retina may be divided into a) an optic portion which participates in the visual mechanism, and b) a non-optic portion which does not participate in the visual mechanism. The optic portion of the retina contains the rods and cones, which are the effectual organs of vision. A number of arteries and veins enter the retina at its center, and splay outwardly to provide blood circulation to the retina.
The posterior portion of the vitreous body is in direct contact with the retina. Networks of fibrillar strands extend from the retina and permeate or insert into the vitreous body so as to attach the vitreous body to the retina. (Sebag, J. Graefe's Arch. Clin. Exp. Ophthalmol. 225, 89-93; 1987)B. The Causes, Treatments and Clinical Sequelae of Rhegmatogenous Retinal Tears, Macular Holes and Cystoid Macular Edema
Diabetic retinopathy, trauma, and other ophthalmological disorders sometimes result in rupture or leakage of retinal blood vessels with resultant bleeding into the vitreous humor of the eye (i.e., “intravitreal hemorrhage”). Such intravitreal hemorrhage typically manifests as clouding or opacification of the vitreous humor.
The human vitreous gel undergoes progressive liquefaction with age. After the age of 40 years, there is a steady increase in observed liquefied vitreous associated with a decrease in vitreous gel volume so that by the age 80 years more than half of the vitreous is liquefied (McLeod, D, et al. Trans. Ophthal. Soc. UK, 1997; 97:225-231). Light microscopic studies of whole human vitreous have demonstrated that vitreous liquefaction initially occurs in pockets, which then coalesce (Sebag. J, et al. Invest. Ophthalmol. Vis. Sci. 1989; 30: 1867-1871). These processes eventually result in rhegmatogenous posterior vitreous detachment (PVD). PVD is usually a sudden event during which liquefied vitreous from the center of the vitreous body bursts through a hole in the posterior vitreous cortex and then dissects the residual cortical gel away from the inner limiting lamina of the retina (Larsson, L. et al. Graefe's Arch. Clin. Exp. Opthalmol. 1985; 223: 92-95). The residual vitreous gel then collapses forward to occupy an anterior position in the vitreous cavity. This process may induce a tear in the retina which, in the presence of residual vitreoretinal traction around the break, can result in rhegmatogenous retinal detachment (McLeod, D. et al. Trans. Opthal. Soc. UK 1997; 97: 225-231). Vitreoretinal traction may also result in macular hole formation and it has been suggested that some forms of cystoid macular edema are due to vitreoretinal traction during incomplete PVD (Sebag, J. et al. Survey Opthalmol. 1984; 28: 493-498). In cases where the rhegmatogenous PVD is accompanied by a retinal tear or detachment, it is important that such retinal tear or detachment be promptly diagnosed and surgically repaired. Failure to promptly diagnose and repair the retinal tear or detachment may allow photoreceptor cells of the retina, in the region of the tear or detachment, to die. Such death of the photoreceptor cells of the retina may result in loss of vision. Furthermore, allowing the retinal detachment to remain un-repaired for such extended period of time may result in further intravitreal hemorrhage and/or the formation of fibrous tissue at the site of the hemorrhage. Such formation of fibrous tissue may result in the formation of an undesirable fibrous attachment between the vitreous body and the retina.
The typical surgical procedure used for repair of retinal tears or detachment requires that the surgeon be able to look through the vitreous humor, to visualize the damaged region of the retina (i.e., “transvitreous viewing of the retina”). When intravitreal hemorrhage has occurred, the presence of the hemorrhagic blood within the vitreous can cause the vitreous to become so cloudy that the surgeon is prevented from visualizing the retina through the vitreous. Such hemorrhagic clouding of the vitreous can take ˜12 months or longer to clear sufficiently to permit trans-vitreal viewing of the retina.
The term Pneumatic Retinopexy was used by Hilton and Grizzard (Hilton, G. F. et al. Ophthalmology 1986; 93: 626-641) as a designation for a nonincisional retinal detachment operation consisting of an intravitreal injection of an expandable gas with cryotherapy and/or photocoagulation of the retinal break(s). Patient positioning oriented the gas bubble to close the retinal break(s), allowing spontaneous resorption of the subretinal fluid. Other authors have reported the complications of subretinal gas (McDonald, H. R. et al. Opthalmology, 1987; 94: 319-326), new retinal break formation (Poliner, L. S. et al. Ophthalmology, 1987; 94: 315-318), macular detachment (Yeo, J. H. et al. Arch. Opthalmol. 1986; 104: 1161-1163) and possible lower success rate in aphakic and pseudophakic eyes (Chen, J. C. et al. Ophthalmology, 1988; 95: 601-608).
Pneumatic Retinopexy is a method of retinal detachment repair which uses cryopexy or photocoagulation in combination with intravitreal gas injection to effect an internal tamponade of retinal breaks. Extension of existing retinal detachments with migration of subretinal fluid into the macula has been reported after pneumatic Retinopexy (Yeo, J. H. et al. Arch. Ophthalmol. 1986; 104: 1161-1163). The present report documents the occurrence of new retinal tears with associated retinal detachment in previously uninvolved quadrants in 20% of the patients within 2-4 weeks of pneumatic Retinopexy (Poliner, L. S. et al. Opthalmology, 1987; 94: 315-318). In these patients the original retinal detachments completely resolved. New retinal tears and associated detachments then developed opposite the original break with vitreous condensation and traction in previously uninvolved quadrants.
The majority of macular holes are “idiopathic” because they occur in eyes that have no previous ocular pathology. Macular holes can form immediately after blunt trauma. Besides trauma, other ocular problems have been associated with macular hole formation, including cystoid macular edema, epiretinal membranes, vitreomacular traction syndrome, rhegmatogenous retinal tears, hypertensive retinopathy, and proliferative diabetic retinopathy (Aaberg, T. M. Survey Opthalmol. 1970; 15: 139-162).
The hallmark complaint of idiopathic macular hole formation is painless central vision distortion or blur of acute or subacute nature. Central visual acuity is initially diminished only mildly; however, as the macular hole progresses over weeks to months, the visual acuity usually deteriorates, then stabilizes around the 20/200 to 20/800 level, and a macular hole diameter of 500 μm.
Examples of substances which have been purported to cause vitreal liquefaction and/or posterior vitreous detachment, or disinsertion are found in the U.S. Pat. Nos. 4,820,516 (Sawyer), 5,292,509 (Hageman), and 5,866,120 (Karageozian et al.).
There exists a need in the prior art for the elucidation and development of new materials and methods for accelerating the liquefaction of the vitreous and the induction of posterior vitreous detachment, or disinsertion of the vitreous.
C. Prior Therapeutic Applications of Urea and Urea Derivatives.
U.S. Pat. Nos. 5,470,881 (Charlton et al.), 5,629,344 (Charlton et al.) have described the topical application to the cornea or the “surface” of the eye of urea and/or urea derivatives to treat ocular conditions such as dryness, non-infectious keratitis, irregularities of the corneal or conjunctival epithelium, ocular scarring and “subjective irritations” of the eye. It is important to note that the urea formulations that have been described in the above mentioned patents utilize formulations which are non-aqueous in nature. These formulations contain hydrophobic non-aqueous systems like white petrolatum, mineral oil, and anhydrous liquid lanolin. Some of the formulations described are aqueous in nature; however, in place of urea the authors suggest the use of urea derivatives like ureidopropionic acid, or allantoin.
In the past, some aqueous urea preparations were reported to hydrolyze, thus producing ammonia as a byproduct. Ammonia is toxic to the eye when applied topically, and is even more toxic when applied intravitreally. Thus,
Urea is a small molecule having a molecular weight of 60.06. Urea is somewhat basic, the pH of a 10% water solution is 7.2. Urea is very soluble in water, ethanol, methanol and glycerol; however, it is practically insoluble in chloroform or ether. Urea is colorless to white, prismatic crystals or white crystalline powder which stored under dry conditions is stable at room temperature. Aqueous urea solutions freshly prepared are clear, colorless and odorless. However, aqueous urea solutions gradually degrade and develop an odor of ammonia.
Urea is a product of the metabolism of proteins in the human body, it is excreted in human urine in average amounts of 30 gm/day. Urea has been widely used in medicine. Urea Solution for Injection has been an Official Monograph in the United States Pharmacopoeia/National Formulary (USP 24, 2000, pp. 1730), for over 40 years. Urea for injection (intravenous) had been a US Food and Drug approved product for over 20 years. The Urea product was registered and sold in the United States by Abbot Pharmaceutical Co. in 1961, under the trade name of Ureaphil. The Physicians' Desk Reference (PDR, Edition 1961, Medical Economics Publishing) lists the Urea for injection 1961 through 1979. References indicate that Urea for Injection was also registered and sold in numerous International countries as an osmotic diuretic for the reduction of intracranial pressure as well as for the reduction of intraocular pressure in subjects with Glaucoma. (Tartar, R. C. et al. American Journal of Opthalmology: 52:323-331; 1961). In addition, urea has been used intravenously to treat painful crisis of sickle-cell disease. (McCurdy, P. R. I.V. “Urea treatment of the painful crisis of Sickle Cell Disease” New England Journal of Medicine. 285: 992-994; 1971).
Urea has been used topically as a dermatological active ingredient in the treatment of Psoriasis, ichthyosis, atopic dermatitis and removal of excess keratin from dry skin. (Remington. “The Science and Practice of Pharmacy” 19 Edition, Chapter 62, pp. 1041-1042, 1995).